Citations

Introduction: Medical education is trending towards an outcome-based curriculum that prepares medical graduates to excel in a rapidly evolving, team-centred healthcare delivery system. The Mayo Medical School (MMS) has recently redesigned its curriculum to introduce early clinical relevance, optimise course integration, provide flexibility and promote active learning. This study aims to evaluate the role that curricular flexibility plays in students’ perceived learning, satisfaction and performance. Materials and Methods: First-year students completed a 5-point Likert scale survey regarding satisfaction with and perceived learning from various components of the flexible curriculum during 2 different academic blocks. Students’ academic performance was assessed by a National Board of Medical Examiners (NBME) Subject Examination after each block. Results: In comparing student-rated satisfaction and perceived learning from didactics versus other curricular components for Block 3 (Pathology and Immunology) and Block 5 (Gross Anatomy and Radiology), students rated didactics higher in all cases in which there was a statistically significant difference in the ratings. There was a statistically significant positive correlation between the amount learned and satisfaction for all curricular components with the exception of Block 5 independent study. During Block 3, only interest in the subject matter correlated positively with the NBME score, while during Block 5, only time spent in class correlated negatively with the NBME score. Conclusions: Although various components of the flexible curriculum do not appear to affect satisfaction and perceived learning, their potential influence on graduate outcomes, in terms of delivering healthcare providers who are patient-centred, creative thinkers and compassionate leaders should not be discounted. Key words: Curriculum reform, Medical curriculum, Outcomes-based education, Student satisfaction

AbstractBackground and AimsIdentifying international differences in utilization and outcomes of liver transplantation (LT) after donation after circulatory death (DCD) donation provides a unique opportunity for benchmarking and population‐level insight.MethodsAdult (≥18 years) LT data between 2008 and 2018 from the UK and US were used to assess mortality and graft failure after DCD LT. We used time‐dependent Cox‐regression methods to estimate hazard ratios (HR) for risk‐adjusted short‐term (0–90 days) and longer‐term (90 days–5 years) outcomes.ResultsOne‐thousand five‐hundred‐and‐sixty LT receipts from the UK and 3426 from the US were included. Over the study period, the use of DCD livers increased from 15.7% to 23.9% in the UK compared to 5.1% to 7.6% in the US. In the UK, DCD donors were older (UK:51 vs. US:33 years) with longer cold ischaemia time (UK: 437 vs. US: 333 min). Recipients in the US had higher Model for End‐stage Liver Disease (MELD) scores, higher body mass index, higher proportions of ascites, encephalopathy, diabetes and previous abdominal surgeries. No difference in the risk‐adjusted short‐term mortality or graft failure was observed between the countries. In the longer‐term (90 days–5 years), the UK had lower mortality and graft failure (adj.mortality HR:UK: 0.63 (95% CI: 0.49–0.80); graft failure HR: UK: 0.72, 95% CI: 0.58–0.91). The cumulative incidence of retransplantation was higher in the UK (5 years: UK: 11.9% vs. 4.6%; p < .001).ConclusionsFor those receiving a DCD LT, longer‐term post‐transplant outcomes in the UK are superior to the US, however, significant differences in recipient illness, graft quality and access to retransplantation were seen between the two countries.

Abstract Objective To evaluate the safety and outcomes of cochlear implantation (CI) in patients with ventriculoperitoneal (VP) shunts to inform clinical practice. Study Design Historical cohort study. Setting Tertiary referral centers. Methods A multi‐institutional historical cohort of patients with VP shunts and CI was identified and analyzed. Results A total of 46 patients (median age 8 years [interquratile range, IQR: 2‐46]) with VP shunts and CI were identified. Of these, 41 (89%) patients had a VP shunt prior to CI. Based on institutional preference and individual patient factors, CI was performed contralateral to a pre‐existing VP shunt in 24 of these 41 cases (59%) and ipsilateral in 17 (41%). Furthermore, pre‐CI relocation of the VP shunt was performed in 3 cases (7%), and 2 patients (5%) underwent planned revision of their VP shunt concurrent with CI. In total, 2 of 27 pediatric patients (7%) required unanticipated revision shunt surgery, both contralateral to CI device placement, given VP shunt malfunction. One of 19 adult patients (5%) required shunt revision during CI due to shunt damage noted intraoperatively. Among 43 patients with available follow‐up, 38 (88%) are regular CI users, with a median consonant‐nucleus vowel‐consonant word: score of 58% (IQR: 28‐72). Conclusion CI can be performed at low risk, either contralateral or ipsilateral, to a VP shunt, and does not mandate shunt revision in most cases. Additional considerations regarding CI receiver‐stimulator placement are necessary with programmable shunts to mitigate device interaction. Preoperative planning, including coordination of care with neurosurgery, is important to achieving optimal outcomes.

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.

AbstractIntroductionEmpathy relies on fronto‐cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress.MethodsFour hundred thirty‐one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non‐carrier controls were enrolled. In sub‐samples, we investigated empathy measured by the informant‐based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51).ResultsEmpathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy.DiscussionLoss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Abstract The consequences of immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) likely relate to the incidence of serious recurrent infections and second malignancies that plague CLL patients. The known immune abnormalities are not able to consistently explain these complications and it is not easy to correct their immune status. Here, we report bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. We found reduced functional capacity of hematopoietic progenitors in BM using colony forming unit assays and flow cytometry revealed significant reductions in frequencies of hematopoietic stem and progenitor cell (HSPC) populations. Consistent with the reduction in HSPCs, monocytes and natural killer cells in BM were reduced and the reduction in BM was recapitulated in blood. Finally, we report imbalances in protein levels of the transcriptional regulators HIF-1α, PU.1, and GATA-2 in CLL patient BM, providing molecular insight into the basis of HSPC dysfunction. Importantly, PU.1 and GATA-2 were rapidly increased when healthy HSPCs were exposed in vitro to TNFα, a cytokine constitutively produced by CLL B cells. Together, these findings reveal BM hematopoietic dysfunction in untreated CLL patients, adding to the complex immunodeficiency state of these patients and the reduced capacity of the innate immune system.

Abstract Tumor cell lysis can be enhanced significantly in vitro when heteroconjugate (HC) antibodies (anti-CD3 x anti-tumor mAb) are used to specifically direct lymphocyte effector cells to the tumor cell target. In order to effectively utilize HC antibodies in an immunotherapy protocol, methods must be identified for the optimum expansion, activation, and retargeting of lymphocyte-effector populations from cancer patients. In this study, we have compared the proliferative responses of different normal and renal cell carcinoma (RCC) patient lymphocyte preparations (PBL, tumor-infiltrating lymphocytes) stimulated in vitro for periods up to 12 days with a variety of growth factor combinations (anti-CD3, rIL-2, rIL-4). These activated lymphocyte preparations were then tested in vitro for their ability to kill RCC tumor cells and tumor cell lines in the presence of HC preparations (anti-CD3 mAb covalently linked to mAb reactive to different RCC tumor-associated Ag). RCC patient PBL cultured with anti-CD3 plus rIL-2 for 12 days resulted in a 3- to 160-fold expansion of effector cells. These cells, as well as tumor infiltrating lymphocytes, when retargeted with appropriate HC antibodies were capable of mediating high levels of killing of autologous tumor cells. No constitutive autologous anti-tumor cell response was detected in the absence of added HC antibodies. Of the five anti-RCC mAb tested (A6H, K29, K20, UR07, and URO 3), HC containing URO 3 x anti-CD3 and K20 x anti-CD3 elicited the highest level of tumor cell lysis by the activated lymphocyte effector cells. Together these results demonstrate that HC antibodies may be a useful imunotherapeutic reagent for directing the killing of RCC tumor cells by autologous lymphocytes.

Abstract A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (ORIVW = 0.87, 95% CI = 0.78, 0.97, P = 0.01), but not in women or in both sexes combined. Τhis association remained consistent in some, but not all, sensitivity analyses and was very similar for colon and rectal cancer. There was no evidence of an association for any other sleep trait. Overall, this study provides little to no evidence of an association between genetically predicted sleep traits and CRC risk.